RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions

Abstract RGD peptide can be found in cell adhesion and signaling proteins, such as fibronectin, vitronectin, and fibrinogen. RGD peptides' principal function is to facilitate cell adhesion by interacting with integrin receptors on the cell surface. They have been intensively researched for use in biotechnology and medicine, including incorporation into biomaterials, conjugation to medicinal molecules or nanoparticles, and labeling with imaging agents. RGD peptides can be utilized to specifically target cancer cells and the tumor vasculature by engaging with these integrins, improving drug delivery efficiency and minimizing adverse effects on healthy tissues. RGD‐functionalized drug carriers are a viable option for cancer therapy as this focused approach has demonstrated promise in the future. Writing a review on the RGD peptide can significantly influence how drugs are developed in the future by improving our understanding of the peptide, finding knowledge gaps, fostering innovation, and making drug design easier.


| INTRODUCTION
Three amino acids compose the structure of the RGD peptide: arginine (Arg), glycine (Gly), and aspartic acid (Asp).The RGD motif is formed by a linear arrangement of these amino acids. 1,24][5] RGD peptides' principal role is to facilitate cell adhesion by binding to the integrin receptors on the cell's surface. 1 Integrins are proteins located in the transmembrane that are essential for cell signaling, motility, and survival.][7][8] In the timeline of RGD peptide, the RGD sequence was first identified as a crucial motif for cell adhesion in the extracellular matrix in 1984.In the 1990s, the RGD peptide began to be modified by scientists to enhance its binding affinity and selectivity to specific integrin receptors.By 1997, biomaterials were incorporated with RGD peptide for tissue engineering, promoting cell adhesion and tissue regeneration.In the early 2000s, the use of RGD peptide as a targeting ligand for drug delivery systems was explored by researchers, enabling specific delivery to cells expressing integrin receptors.In 2010, RGD peptide-conjugated nanoparticles were developed for targeted delivery of anticancer drugs to tumor cells, showing promising results in preclinical studies.Since 2015, RGD peptide has also been utilized in the development of scaffolds and hydrogels for tissue engineering applications, facilitating cell adhesion and promoting tissue regeneration.In 2020, RGD peptide was incorporated into bioinks used in 3D bioprinting, enabling precise deposition of cells and promoting their attachment to the printed structures.They found that these integrins bind to their native ligands that contain the RGD sequence.This discovery opened up new possibilities for utilizing RGD peptides as targeting motifs in cancer treatment for both therapeutic and diagnostic purposes.The absence of intellectual property protection further fueled the development of various RGD-based agents, including fluorescence markers, radiopharmaceuticals, drug conjugates, nanoparticles, and micelles.While RGD applications related to angiogenesis and αvβ3integrin have been prominent in the field of radiopharmacy, it is important to note that RGD is not limited to these specific targets.Researchers have also explored the affinity and selectivity of RGD peptides for other integrins, such as αvβ6integrin.The development of radiolabeled ligands targeting αvβ3integrin has been a significant breakthrough in radiotheranostics for cancer therapy.The future of RGD in targeted cancer therapy holds great promise.Ongoing research is focused on the continuous development of novel RGD-based ligands and exploring the potential of integrins in therapy.RGD peptides may find applications beyond cancer therapy, including in the field of cancer immunotherapy.0][11][12][13][14][15] RGD peptides can be modified to enhance its anticancer properties.A few Examples of RGD analogues that were used for the targeting cancer were depicted in Figure 1.
Specific integrins identify the RGD motif within proteins and bind to this peptide, allowing cell adhesion and communication.7][18][19] To increase cell adhesion and growth, RGD peptides can be introduced into biomaterials such as hydrogels and scaffolds.5][26][27] Integrins, notably αvβ3 and αvβ5, are elevated in malignant cells and vasculature.The medicine may be administered selectively to the tumor location by connecting RGD peptides to drug carriers, limiting the impact on normal cells and tissues.RGD peptides can help drug carriers get into cells by engaging with integrin receptors, which are found on the cell's surface.9][30][31] This is especially effective for delivering drugs with low cell permeability or that breakdown quickly in the extracellular environment.RGD-functionalized drug carriers can be engineered to carry numerous therapeutic agents to the target area, such as chemotherapeutic medicines and genes.This can aid in the treatment of drug resistance and improve the overall therapeutic impact.
3][34] This can guarantee that the medicine is only delivered at the intended spot, reducing adverse effects, and boosting therapeutic efficacy.6][37] This can aid in identifying and monitoring illnesses caused by aberrant integrin expressions, such as cancer and cardiovascular disease.Furthermore, RGD peptides can be combined with imaging agents to allow for real-time monitoring of drug distribution and treatment response.][40][41][42] By inhibiting the interaction between integrins and their ligands, RGD peptides can be utilized alone to limit tumor development and angiogenesis.This has the potential to alter signaling pathways involved in cancer cell survival, migration, and invasion.Angiogenesis inhibition is a viable treatment option for cancer and other disorders characterized by excessive blood vessel formation.][45][46] RGD peptides, RGD peptide-conjugated medicines, and RGD peptide-conjugated nanoparticles/nanocarriers have considerable potential for targeted drug delivery and imaging.Their capacity to selectively target integrin-expressing cells may result in better treatment results, fewer side effects, and enhanced disease identification and monitoring.New medications targeting the RGD peptide have the potential to enhance the lives of millions of individuals suffering from illnesses such as cancer, cardiovascular disease, and inflammatory ailments.A thorough review can aid in the consolidation of existing information regarding RGD peptides, their interactions with integrins, and their significance in many biological processes.This can serve as a good basis for researchers to find new therapeutic targets.A review of RGD peptides can have a substantial influence on future drug development by improving our understanding of the peptide, revealing knowledge gaps, promoting innovation, and aiding drug design.

| OVEREXPRESSED INTEGRINS FOR RGD PEPTIDE-BASED CANCER THERAPIES
A class of cell surface receptors known as integrins is essential for cell adhesion, migration, and signaling.They are heterodimeric proteins composed of two subunits, α and β, which come together to create different integrin pairs.8][49] Integrins that recognize the RGD motif particularly interact with the RGD peptide.6][57] RGD peptides that target the αvβ3 integrin can aid in preventing tumor angiogenesis, invasion, and proliferation.9][60][61] To stop the creation of new blood vessels and restrain tumor growth, RGD peptides can interfere with this integrin's function.3][64][65] RGD peptides can help stop cancer cells from migrating and invading by targeting the α5β1 integrin.7][68] Cancer cell invasion and metastasis include the αvβ6 integrin.It is possible to stop the spread of cancer by targeting this integrin using RGD peptides.The surface of platelets expresses the αIIbβ3 integrin, which is essential for platelet aggregation.Even while platelet aggregation is not directly connected to tumor cells, tumor cells can use it to encourage metastasis.0][71][72] RGD peptides can be utilized to specifically target cancer cells and the tumor vasculature by engaging with these integrins, improving drug delivery efficiency, | 5 of 44 and minimizing adverse effects on healthy tissues.RGDfunctionalized drug carriers are a viable option for cancer therapy since this focused approach has demonstrated promise in studies.

| RGD PEPTIDES: CHALLENGES
The potential applications of the RGD peptide in cancer targeting have garnered significant attention within the field of cancer research.The discovery of the RGD peptide's cancer targeting properties has opened up novel avenues for the precise delivery of drugs and imaging agents in cancer therapy.By linking anticancer drugs or imaging agents to the RGD peptide, cancer cells can be specifically targeted while minimizing harm to healthy cells.This targeted approach holds promise for improving the effectiveness of cancer treatments and reducing undesirable side effects.Additionally, the RGD peptide can be employed in the development of imaging agents that are specific to cancer.][75][76] RGD peptides are derived from natural proteins, which may trigger an immune response in some patients (Table 1, Figure 3).8][79][80] Peptides, including RGD peptides, can be susceptible to degradation by proteases in the body.2][83] To overcome this issue, researchers often use modified or cyclic RGD peptides, which exhibit increased stability and resistance to protease degradation.5][86] This may limit the widespread adoption of RGD peptide-based drug delivery systems.Integrin expression can vary between different types of cancer and even between individual tumors of the same type. 66,87This heterogeneity may affect the effectiveness of RGD peptide-based drug delivery, as the therapy may be more effective in some patients than in others.

IMMUNOGENICITY
To overcome the potential immunogenicity of RGD peptides, altering the peptide structure can help reduce immunogenicity.For example, enlarging the peptide ring of c(RGDyK) by introducing an amino sequence serine-glycine-serine (SGS) has been shown to reduce the incidence of anaphylaxis after repeated intravenous c(RGDyKSGS)-liposome stimulation. 79This modification was effective in reducing the incidence of anaphylaxis post the repeated intravenous c(RGDyKSGS)-liposome stimulation.Therefore, the introduction of the SGS sequence into c(RGDyK)-liposomes serves as a strategy to mitigate the immunogenicity-associated issue and enhance the safety profile of these drug delivery systems.9][90] This approach can also prolong the circulation time of the RGD peptide in the bloodstream, allowing for more effective delivery to the target site.A promising strategy for attenuating the immune response is presented when RGD peptide-based lipids are combined with immunosuppressive agents.This approach was exemplified by the study mentioned in the provided document, where RGD-modified lipid nanoparticles (LNPs), specifically RGD-PEG-lipid modified through the post-insertion method, were utilized.This modification allowed the nanocarrier system to be preferentially targeted toward integrin-expressing tumor endothelial cells (TECs).In a recent study, an immunosuppressive agent, aPD-1 monoclonal antibody (mAb), was employed.The programmed cell death protein 1 (PD-1) receptor, a key regulator of T-cell responses, was inhibited by this antibody, thereby enhancing antitumor immune responses.By combining RGD-modified LNPs with aPD-1 mAb and siVegfr2 (small interfering RNA against Vegfr2), a reduction in tumor-infiltrating lymphocytes (TILs), indicative of immune response mitigation, was achieved.Furthermore, vascular normalization was induced, and tumor growth was suppressed through this combination approach.It is worth noting that RGD-PEG-lipid was the lipid utilized in the study, and aPD-1 mAb was the specific immunosuppressive agent employed.This strategy, which involves the utilization of RGD peptide-based lipids and immunosuppressive agents, aligns with the broader goal of improving the efficacy of gene therapy while mitigating potential adverse immune reactions.It thus represents a promising avenue for further exploration in cancer treatment. 91,924][95] The choice of delivery system can have a significant impact on the immunogenicity of RGD peptides, which may include liposomes, nanoparticles, and micelles, etc.It is needed to find the most suitable T A B L E 1 The possible issues, effects, and possible related solutions.

Induction of an immune response through T-cell activation
Production of anti-RGD antibodies Using modified versions of the RGD peptide that cannot activate T-cells or are less immunogenic.
The immune response may affect the efficacy of RGD peptide-based therapies Pretreatment of patients with immunosuppressive drugs.

Repeated exposure to RGD peptide
Chronic immune responses and severe adverse reactions Functionalizing RGD peptide with biocompatible polymers or coatings to reduce immune recognition and increase the lifespan of the peptide.

Altered conformation of the RGD peptide
The induction of new antigenic epitopes that can provoke an immune response Choosing a suitable delivery system that can protect the RGD peptide from immune recognition.

Purity and quality of the RGD peptide
Presence of contaminating antigens that can trigger an immune response Using high-quality RGD peptide products that meet the regulatory standards for purity and absence of contaminants.

Short half-life
Rapid degradation by proteases Conjugation to protein carriers or nanoparticles to increase stability and half-life.

Low solubility
Poor bioavailability Chemical modifications to improve solubility and reduce protease susceptibility.

Rapid degradation
Encapsulation in liposomes or other drug delivery systems to protect against degradation.

Lack of target specificity
Use of site-specific targeting approaches.
High toxicity in some cases Modification of the peptide sequence to reduce toxicity.
The complexity of the peptide structure and synthesis Develop more efficient synthetic methods using specialized reagents and devices.
High synthesis cost and low yields.
Optimize the reaction parameters such as temperature, pH, and concentration to improve yields and reduce cost.
Difficulties in developing scalable synthesis methods.Implement automation techniques to reduce handling errors and increase throughput.
Limited availability of amino acid building blocks.Improve the availability and cost of amino acid building blocks by developing new synthetic routes or using alternative sources.
The need for multiple purification steps to obtain high purity.
Develop novel purification techniques such as immobilized-metal affinity chromatography or reversephase high-performance liquid chromatography to reduce the number of steps required for purification.
Heterogeneity of integrin expression on different cell types and within a single cell type.
Using integrin-specific antibodies or aptamers to capture or target specific integrin-expressing cells.
Variable affinity and selectivity of RGD peptides for different integrin subtypes.
Design and optimize RGD peptides with higher affinity and selectivity for a specific integrin subtype by modifying the peptide structure.
RGD peptide internalization and degradation by cells.Use modified RGD peptides or peptide conjugates that are resistant to degradation and can prolong integrin binding.
Competition for integrin binding by other ligands in the extracellular matrix.
Combine the RGD peptide with other proteins or peptides that can selectively compete for the binding sites of integrins and enhance RGD peptide binding.
Poor penetration of RGD peptides into solid tumors or tissues.
Combine the RGD peptide with nanocarriers, such as liposomes or nanoparticles, to improve delivery and penetration into target tissues.

| 7 of 44
7][98][99] Considering the diversity of major histocompatibility complex (MHC) alleles in different populations and races, designing personalized peptides based on an individual's MHC profile can help reduce the risk of immunogenicity. 100It is essential to carefully evaluate each approach's benefits and drawbacks to determine the most suitable method for a specific application.

| LIMITED STABILITY
The RGD peptide's poor solution stability can be overcome by cyclizing the linear RGD peptide. 101,102It can improve its stability greatly by lowering conformational flexibility and making it less sensitive to proteolysis.A covalent link is formed between two amino acids in the linear sequence to accomplish cyclization.Multiple copies of RGD sequences incorporated into a single molecule can boost their affinity for integrin receptors, compensating for lower individual binding affinities.Multimeric structures incorporating surface-bound RGD peptides, such as dendrimers or nanoparticles, have shown increased biological activity.4][105][106] PEGylation protects peptides from enzymatic breakdown while retaining bioactivity.][107] Co-administration or conjugation with serpins may protect the peptide against early hydrolysis by inhibiting the breakdown of enzymes. 108,109Serpins, also known as serine protease inhibitors, are a superfamily of proteins that play a crucial role in regulating protease activity.They are characterized by a conserved structure and mechanism of action.Serpins inhibit serine proteases by forming a covalent complex with the protease, leading to its inactivation.This interaction involves a reactive center loop (RCL) within the serpin molecule that acts as a bait for the protease.Serpins are involved in various physiological processes, including blood clotting, immune response, and inflammation.They also have implications in diseases such as cancer, thrombosis, and neurodegenerative disorders. 109Chemical changes such as N-methylation or D-amino acid substitution to particular amino acids within an RGD motif may assist increase resistance to enzymatic cleavage without reducing receptor affinity.Non-peptide analogs or peptidomimetics that replicate the structure and function of the RGD peptide can improve stability, bioavailability, and potency.1][112] It is feasible to overcome the restricted stability of RGD peptides while retaining their biological activity for diverse therapeutic purposes by using these tactics singly or in combination.

SYNTHESIS CHALLENGES OF RGD PEPTIDE
Due to the necessity for specialized modifications or multimeric structures, the synthesis of RGD peptides can be complicated, time-consuming, and expensive.To address these obstacles, new RGD motifs with simpler structures or more accessible synthetic methods may provide equal biological activity while lowering synthesis complexity and expense. 4,25,113,114olid-phase peptide synthesis (SPPS) provides for the effective step-by-step assembly of amino acids on a solid platform, eliminating purification stages and enhancing total yield.Automated SPPS synthesizers reduce manual effort and human error even further.Adjusting reaction parameters such as temperature, solvent choice, coupling reagents, or protecting groups may increase peptide synthesis efficiency and prevent side reactions that cause contaminants.Continuous improvement in production procedures through optimization studies will increase process efficiency, resulting in less waste, higher product quality, and lower cost per unit.][130] By adopting these strategies individually or in combination, it is possible to overcome the complexity and cost challenges associated with the synthesis of RGD peptides without compromising their therapeutic potential.

INTEGRIN EXPRESSION CHALLENGE OF RGD PEPTIDE
Heterogeneous expression of integrins on different cell types and tissues can impact the targeting specificity and therapeutic efficacy of RGD peptides.To overcome this challenge, design RGD peptide derivatives that selectively target specific integrin subtypes overexpressed in pathological conditions such as cancer or inflammation. 131his can be achieved by modifying amino acid sequences, incorporating additional functional groups, or using peptidomimetics.
The application of targeted extracellular matrix (ECM)-derived peptides for promoting neovascularization in a rodent model of myocardial infarction is the focus of the document.One specific approach mentioned in the document is the conjugation of targeting moieties, such as antibodies or aptamers, to RGD peptide constructs.The interaction of the RGD peptide sequence with integrin receptors on the surface of cells is well-known.By conjugating targeting moieties, such as antibodies or aptamers, to RGD peptide constructs, the specificity of the peptides toward cells with co-expression patterns related to disease conditions is increased.This results in an increased likelihood of the peptides binding to and interacting with cells specifically involved in the disease process, such as cells in the infarcted area of the heart.The reduction of off-target effects on normal cells is achieved by increasing the specificity of the peptides.This is important as it minimizes any potential negative impact on healthy cells and tissues.The conjugation of targeting moieties to RGD peptide constructs enables a more precise and targeted delivery of the peptides to the desired cells, thereby enhancing their therapeutic potential.Hence, a promising strategy for improving the specificity and effectiveness of ECM-derived peptides in promoting neovascularization in the context of myocardial infarction is offered by the approach of conjugating targeting moieties to RGD peptide constructs.Conjugating other targeting moieties (e.g., antibodies, aptamers) to RGD peptide construct increases specificity toward cells with co-expression patterns related to disease conditions while reducing off-target effects on normal cells. 1324][135] Nanoparticles and nanocarriers could utilize engineered surface-bound RGD motifs for enhanced cellular uptake via receptor-mediated endocytosis while carrying a therapeutic payload within the core/shell matrix. 134,136][142] Identifying biomarkers indicative of high integrin expression levels corresponding to likely responders allows for better patient stratification and personalized treatment approaches.7][148] By employing these strategies individually or in combination, it is possible to overcome challenges posed by heterogeneous integrin expression when using | 9 of 44 RGD peptides for targeted therapies while maximizing their clinical potential. 8| SOME AVAILABLE RGD -BASED DRUGS RGD peptides are short peptide fragments derived from the amino acid sequence of several extracellular matrix proteins, such as fibrinogen, fibronectin, vitronectin, collagen, and laminin.They are widely present in fibronectin, laminin, fibrinogen, osteopontin, and vitronectin.
RGD can be divided into two types: 1. RGD: This is a tripeptide sequence of RGD.
2. RGD polypeptide: This is a functional peptide containing RGD.
Depending on the application and the integrin targeted, RGD can be chemically modified or replaced by a similar peptide which promotes cell adhesion.For example, RGD peptides can be cyclized, or made into a cyclic compound, via disulfide, thioether, or rigid aromatic ring linkers.This leads to an increase in binding affinity and selectivity for integrin αVβ3 relative to αIIBβ3.
Another type of RGD-derived peptide is the "internalizing RGD" or "iRGD."][151][152][153][154] Cilengitide is a cyclic RGD peptide that targets αvβ3 and αvβ5 integrins (Figure 4).It has been investigated as a potential treatment for glioblastoma, a type of brain cancer.Cilengitide has shown promising results in preclinical studies (Table 2), but its efficacy in clinical trials has been limited.6][157] Eptifibatide is also a cyclic RGD peptide that targets αIIbβ3 integrin, which is involved in platelet aggregation.Eptifibatide is used as an antiplatelet agent to prevent blood clots in patients with acute coronary syndrome or undergoing percutaneous coronary intervention.][160][161] Abegrin is a cyclic RGD peptide that α v β3 integrin, which is overexpressed in several types of cancer.Abegrin has been investigated as a potential treatment for various cancers, including breast cancer and pancreatic cancer.The associated clinical trials can be found in Table 3.One advantage of Abegrin is its high specificity for α v β3 integrin, which can improve the efficacy of the therapy. 9,162-164

CLINICAL TRIALS
The clinical studies focus on various types of cancer, including ovarian cancer, lung cancer, head and neck cancer, glioblastoma, non-small cell lung cancer, cervical cancer, and others.Each study aims to evaluate the specific application of the drugs in the context of these cancer types.The studies utilize different imaging techniques, such as PET/CT (positron emission tomography/computed tomography) and PET/MRI (positron emission tomography/magnetic resonance imaging), to assess tumor characteristics, angiogenesis, and response to treatment.These imaging techniques provide valuable information about the distribution and activity of the drugs within the body.Some studies have secondary objectives, such as evaluating immunologic responses, determining potential toxicities, assessing the predictive value of imaging techniques, and correlating imaging parameters with clinical treatment response (Table 4).
RGD-based radiopharmaceuticals are designed to specifically target integrin αvβ3 receptors.These receptors are proteins found on the surface of cells, including cancer cells and activated endothelial cells involved in angiogenesis.The RGD sequence has a specific structure that allows it to bind to these receptors.To enable imaging of tumor angiogenesis, the RGD-based radiopharmaceuticals are labeled with short half-life isotopes like 68 Ga and 99m Tc (Table 4).These isotopes emit positrons (in the case of 68 Ga) or gamma rays (in the case of 99m Tc).PET/CT or SPECT/CT imaging techniques are used to detect and capture these emissions.By administering the radiopharmaceuticals to patients and performing PET/CT or SPECT/ CT scans, it becomes possible to visualize and quantify the extent and characteristics of tumor angiogenesis.This imaging approach provides valuable information for various aspects of cancer management.First, it aids in cancer diagnosis by providing detailed images that can help identify the presence and location of tumors.It can also assist in staging, which involves determining the extent and spread of the disease.Furthermore, this imaging technique is useful in treatment planning.By visualizing tumor angiogenesis, healthcare professionals can better understand the blood supply to the tumor and make informed decisions regarding treatment strategies.It can help determine the most appropriate treatment approach, such as the use of chemotherapy, radiation therapy, or targeted therapies.Additionally, molecular imaging of tumor angiogenesis using RGD-based radiopharmaceuticals allows for the monitoring of therapeutic response.By comparing images taken before and after treatment, healthcare professionals can assess the effectiveness of the chosen treatment and make adjustments if necessary.Hence, RGD-based radiopharmaceuticals, labeled with short half-life isotopes like 68 Ga and 99m Tc, target integrin αvβ3 receptors.This enables molecular imaging of tumor angiogenesis using PET/CT or SPECT/CT imaging techniques.By visualizing and quantifying the extent and characteristics of tumor In the safety run-in 12 subjects were included and evaluated for safety and feasibility of different escalating doses of cilengitide administered twice weekly in combination with cetuximab, cisplatin and vinorelbine or gemcitabine.
After completion of the safety run-in, the randomized part will be started, during which all subjects will receive cetuximab and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/ gemcitabine).
Subjects will be centrally randomized on a 1:1 basis to either Group A or C; Group B will be closed with implementation of Amendment No.The decision which of the 2 chemotherapy regimens will be applied for a given subject is at the discretion of the treating investigator.
Group B will be closed with implementation of Amendment No. 4 (global, dated December 20, 2010).Subjects randomized to Group B before implementation of Amendment No 4 will continue to be treated as planned.
â€¢ Group C: cetuximab and platinum-based chemotherapy as described for Group A Chemotherapy will be given until radiographically documented progressive disease (PD) or unacceptable toxicity but for no more than 6 cycles.
Cilengitide and cetuximab will be given until radiographically documented PD or unacceptable toxicity.
Randomization will be performed centrally using an interactive voice/web response system (IXRS).A stratified block randomization procedure will be employed using chosen first-line chemotherapy (cisplatin/vinorelbine vs. cisplatin/gemcitabine) as stratification criterion.The MGMT gene promoter is a section of deoxyribonucleic acid (DNA) that acts as a controlling element in the expression of MGMT.Methylation of the MGMT gene promoter has been found to appear to be a predictive marker for benefit from temozolomide (TMZ) treatment.
In a safety run-in period in dedicated study centers, the safety and tolerability of cilengitide given as an intense treatment in combination with the first part of standard therapy will be assessed.Thereafter the trial will investigate the overall survival and progression-free survival in subjects receiving two different regimens of cilengitide in combination with standard treatment versus standard treatment alone.

Terminated
The main purpose of this clinical trial is to find out if cilengitide has an effect on brain tumor cells but also particularly on the blood vessels supplying the tumor with nutrient and oxygen in patients newly diagnosed with non-resectable (inoperable) glioblastoma.
In addition, this clinical trial will investigate if the addition of cilengitide in combination with standard treatment prolongs life in patients with non-resectable glioblastoma.Similarly, the duration of response of the cancer to this treatment and the side effects of the therapy will be analyzed.Furthermore, additional data on how the body deals with this substance will be collected (this is called pharmacokinetics or pharmacokinetic (PK) analysis).In this clinical trial the investigators would also like to learn more about the disease and the response to the experimental medication by measuring certain "markers." This imaging trial will investigate the biological effects of cilengitide monotherapy on the tumor microvascular function and tumor viability in a homogenous non-pretreated subject population with newly diagnosed gliobastoma (GBM).The purpose of this clinical trial is to study the effect that cilengitide may have on certain markers of cancer in your tumor and/or blood and to learn if there are any disease-related markers that could help in predicting how subjects respond to the administration of cilengitide.

Completed
The purpose of this open-label, randomized, controlled, Phase 1/2 study of the integrin inhibitor cilengitide is to evaluate the safety and efficacy of the combination of different regimens of cilengitide added to cisplatin, 5-fluorouracil (5-FU), and cetuximab in participants with recurrent/ metastatic squamous cell carcinoma of the head and neck (SCCHN).
The Phase 1 part was conducted in dedicated study centers.In the Phase 2 part of this trial, cilengitide is administered at two different doses to two experimental groups.The third group will only receive cisplatin, 5-FU and cetuximab.In the Phase 1 part of this trial, the dose of cilengitide in combination with cisplatin, 5-FU, and cetuximab was determined.
Cilengitide is an experimental anticancer substance interacting with so-called integrins.Integrins are protein molecules that are known to be present on the surface of certain cancer cells.Integrins are also found on certain cells that belong to growing blood vessels (endothelial cells).Integrins potentially facilitate the blood vessels' support of the tumor (angiogenesis) as well as the tumor's growth and further spread throughout the body (metastasis).By inhibiting integrins on the tumor cell surface, cilengitide potentially kills cancer cells, and potentially sensitizes cancer cells to other co-administered therapeutics.By inhibiting integrins on the endothelial cell surface, it potentially inhibits the ingrowth of additional blood vessels toward the tumor.
Cilengitide is given as an intravenous infusion (given by a drip in one vein of your arm).If any unacceptable side effect occurs, treatment with the study drug will be stopped.Eligible patients are included according to a standard 3

YES
Patients included in the trial will be treated with a combination of radiochemotherapy (standard radiotherapy of 66 Gy, 2 Gy per daily fraction, and cisplatin and vinorelbine-based chemotherapy).
Cilengitide will be administered alone as continuous infusion two weeks before the radiochemotherapy and will then be continued during radiochemotherapy as continuous infusion.
The dose levels investigated will be applied to the continuous administration (a maximum of 4 dose levels).
After the end of concomitant radiochemotherapy, cilengitide will be administered i.v. at a dose of 2000 mg twice weekly until the end of chemotherapy.
The dose of Cilengitide administered after radiotherapy will not be increased.

Completed
This is an open-label, single-arm study to explore whether 18F-ALF-NOTA-PRGD2 PET/CT scan can predict the efficacy and adverse events of apatinib in patients with malignancies.
Integrin Î ± vÎ 2 3 has been shown to play an important role in angiogenesis and up-regulated obviously in various types of tumor cells and activated endothelial cells.The arginineglycine-aspartic acid (RGD) tripeptide sequence can bind to integrin Î ± vÎ 2 3 with high affinity and specificity.
In the current study, investigators propose to evaluate the feasibility of 18F-RGD PET/CT in monitoring efficacy and adverse events of apatinib in malignancies.into brain tissue will be followed by up to two 28days cycles of oral temozolomide (TMZ) in schedule of 7 days on/7 days off to evaluate safety of the combination.Completion of two full cycles of TMZ will be dependent upon tolerance and toxicity.
The rationale in using the virus with chemotherapy begins with the lessons learned in many clinical trials in glioblastoma (GBM) about both the great difficulty of treating this disease with monotherapy and the limitations of the therapeutic virus.The best clinical results in recent years have been achieved with combinations of multiple therapeutics efforts, including, maximum resection and chemotherapy, immunotherapy, and targeted therapies.
There are very strong preclinical data about the synergy of DNX-2401 and TMZ proposed in our trial design.The dosedense schemes of TMZ like the one we will use, have been developed with the aim to saturate o6-methylguanine-

DNA-methyltransferase (MGMT). The published results
to date have shown reasonable toxicity albeit with modest efficacy' these schemes are now in Phase III trials.In addition, autophagy triggered by TMZ could help viral replication in the tumor cells 11.
The last argument in favor of this virus is the proved efficacy in killing GBM tumor stem cells.In vitro and animals models have shown this combination is much more effective that any of the treatments alone against GBM stem cells and the tumors derived from them.angiogenesis, this imaging approach provides valuable information for cancer diagnosis, staging, treatment planning, and monitoring of therapeutic response.It offers insights into the biology and behavior of tumors, aiding in cancer management and treatment decision-making.Additionally, conditionally replicative adenoviruses (CRAds) are a type of adenovirus that have been genetically modified to selectively replicate in cancer cells while sparing normal cells.This targeted replication within cancer cells can lead to their destruction and potentially provide a therapeutic benefit.One specific type of CRAd mentioned in Table 4 is Ad5-Delta 24RGD.This CRAd is designed to infect and replicate within cancer cells that overexpress integrin αvβ3 receptors, which are commonly found on the surface of tumor cells.By targeting these receptors, Ad5-Delta 24RGD can selectively infect and replicate within cancer cells, leading to their destruction.Another CRAd mentioned is DNX-2401.This CRAd is being evaluated in clinical trials for the treatment of glioblastoma, a type of aggressive brain cancer.DNX-2401 is delivered directly into the tumor, either through intratumoral injection or into the resected tumor cavity.Once inside the tumor, DNX-2401 can replicate and spread, targeting and destroying cancer cells.In addition to glioblastoma, CRAds are also being studied in various types of cancer, including ovarian cancer.Clinical trials are being conducted to evaluate the safety, tolerability, and efficacy of CRAds in these cancer types.These trials aim to determine the appropriate dosing, administration routes, and potential side effects of CRAds in order to assess their therapeutic potential.By selectively targeting cancer cells and replicating within them, CRAds have the potential to provide a targeted and effective treatment approach for various types of cancer.However, it is important to note that clinical trials are still ongoing, and further research is needed to fully understand the safety and efficacy of CRAds in different cancer types.
Apatinib is an antiangiogenic drug that selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2).VEGFR-2 is a protein that plays a crucial role in angiogenesis, the process by which new blood vessels are formed to supply nutrients and oxygen to tumors.
By specifically targeting and blocking VEGFR-2, apatinib disrupts the signaling pathway that promotes angiogenesis.This inhibition of angiogenesis can help to starve tumors of their blood supply, potentially slowing down their growth and progression.Clinical studies are currently being conducted to evaluate the efficacy and safety of apatinib in patients with different malignancies.These studies aim to assess the drug's ability to inhibit angiogenesis and its impact on tumor growth and patient outcomes.In the context of molecular imaging, 18F-ALF-NOTA-PRGD2 PET/CT scans are being used in these clinical studies to predict the response to apatinib treatment.PRGD2 is a peptide that specifically binds to integrin αvβ3 receptors, which are overexpressed in tumor-associated blood vessels.By labeling PRGD2 with the radioactive isotope 18F and performing PET/CT scans, researchers can visualize and quantify the expression of integrin αvβ3 receptors in tumors.These PET/CT scans provide valuable information about the extent and characteristics of tumor angiogenesis, which can help predict the response to apatinib treatment.By assessing the level of integrin αvβ3 receptor expression, researchers can gain insights into the tumor's angiogenic activity and its potential sensitivity to apatinib therapy (Table 4).

COMPETE WITH RGD
The RGD peptide is one of the most commonly used peptides for targeted cancer therapy.The RGD peptide has a high affinity for integrin receptors, which are overexpressed on the surface of many cells.Other peptides can compete with RGD for integrin receptor binding and have been investigated for targeted cancer therapy.9][170] However, the RGD peptide remains one of the most widely studied and utilized peptides for targeted cancer therapy due to its high affinity for integrin receptors and its ability to selectively target tumor cells (Table 5).

| iRGD PEPTIDE
The iRGD (internalizing RGD) peptide is a modified version of the traditional RGD peptide with an amino acid sequence: CRGDKGPDC.2][173] Following proteolytic cleavage of the iRGD peptide after binding to integrins, a CendR motif (Cterminal arginine or lysine residue) is exposed which interacts with neuropilin-1 (NRP-1) receptors present on tumor cells and vasculature, leading to enhanced tissue | 31 of 44 T A B L E 5 The application of different pedtides in therapies.

Peptide's type
Applications Explanation

RGD peptide
Specificity RGD peptides have high specificity toward fibronectin receptors and can selectively bind to them.
Biocompatibility RGD peptides are biocompatible and do not cause any adverse immune response in the body.
Tissue regeneration RGD peptides promote tissue regeneration by stimulating cell growth, differentiation, and migration.
Wound healing RGD peptides stimulate angiogenesis and improve wound healing by increasing the supply of oxygen and nutrients to the wound site.
Anti-inflammatory RGD peptides possess anti-inflammatory properties and can mitigate the inflammatory response in the body.
Antitumor RGD peptides inhibit tumor growth and metastasis by preventing the formation of new blood vessels.
Drug delivery RGD peptides can be used as a targeted drug delivery system to deliver drugs specifically to the site of interest.
Imaging RGD peptides can be used for imaging purposes to detect cancer cells and other abnormalities in the body.
Safe RGD peptides are safe and have been extensively studied for their use in various medical applications.
Noninvasive RGD peptides are non-invasive and can be administered topically or orally, making treatment less painful and more convenient.

NGR peptide
Tumor-targeting NGR peptides specifically bind to overexpressed CD13 or aminopeptidase N on tumor cells, which can help target the delivery of drugs to these cells.
Low toxicity NGR peptides have been shown to be safe and well-tolerated in both animal and human studies.

Enhanced drug delivery
NGR peptides have been shown to enhance the delivery of a variety of drugs to tumor cells, including chemotherapy agents, radioisotopes, and gene therapy.
Antiangiogenic effects NGR peptides have been shown to inhibit angiogenesis or the formation of new blood vessels, which can help prevent tumor growth and metastasis.
Immunostimulatory effects NGR peptides have been shown to activate the immune system and induce antitumor immune responses, which can help eradicate tumors and prevent recurrence.

Increased therapeutic efficacy
NGR peptides can improve the efficacy of various cancer treatments and increase patient survival rates.

iRGD peptide
Enhanced tumor penetration iRGD peptides improve the penetration of therapeutic agents into tumors by enhancing their binding to tumor-specific receptors and enabling them to diffuse more deeply into the tumor microenvironment.

Lower toxicity
The improved tumor penetration of iRGD peptides allows for lower doses of therapeutic agents to be used, reducing the risk of toxicity and side effects.
Increased efficacy RGD peptides improve the delivery of therapeutic agents to tumor cells, increasing their efficacy in killing cancer cells and reducing the potential for drug resistance.
Targeted delivery iRGD peptides specifically bind to tumor cells, allowing for targeted delivery of therapeutic agents to the site of the tumor, reducing the potential for off-target effects on healthy cells.
Improved imaging iRGD peptides can be used in imaging studies to improve the detection and localization of tumors, facilitating more accurate diagnosis and treatment planning.

Improved prognosis
The increased efficacy of iRGD peptides in delivering therapeutic agents to tumors can potentially improve patient outcomes and prognosis.
5][176][177] Potential applications of iRGD peptides in cancer treatment include conjugating chemotherapy agents or cytotoxic drugs for targeted delivery, coupling with nanoparticles or nanocarriers for efficient drug transport, enhancing gene therapy approaches by conjugating viral vectors or gene-editing tools and boosting immunotherapy efficacy through targeted delivery of immune checkpoint inhibitors.

| CRGDK PEPTIDE
The CRGDK peptide is a pentapeptide containing an RGD sequence flanked by cysteine residues at both ends, resulting in improved stability due to cyclization via disulfide bond formation.][180] Both iRGD and CRGDK peptides are derived from the RGD peptide family but possess unique properties that can be exploited for various treatment purposes.The iRGD peptide demonstrates improved tumor targeting and penetration abilities via dual receptor binding (integrins and NRP-1), while the cyclic structure of CRGDK offers enhanced stability against proteolytic degradation.
Each peptide has potential applications in targeted chemotherapy, nanoparticle-based drug delivery systems, gene therapy, and immunotherapy approaches for cancer treatment.

| INTERACTION BETWEEN THE RGD MOTIF AND INTEGRIN
Integrins are heterodimeric proteins composed of α and β subunits.In humans, there are 18 α subunits and 8 β subunits, which can combine to form different integrin receptors.The extracellular domain of integrins contains a ligand-binding head region, a single-pass transmembrane domain, and a cytoplasmic tail that interacts with intracellular signaling molecules.The ligand-binding head region consists of a βpropeller domain and a βIlike domain, which together form a binding pocket for the RGD motif.The RGD motif is a short peptide sequence found in various ECM proteins, such as fibronectin, vitronectin, and collagen.It plays a crucial role in cell adhesion and migration by interacting with integrin receptors.][183] The interaction between the RGD motif and integrin receptors is a multistep process.Initially, the RGD motif binds to the ligand-binding head region of the integrin receptor, primarily through interactions with the α subunit.This binding induces conformational changes in the integrin, leading to the exposure of a high-affinity

Peptide's type
Applications Explanation

CRGDK peptide
Anti-inflammatory properties CRGDK peptide has been shown to have anti-inflammatory properties, which can be beneficial in the treatment of a variety of inflammatory diseases.
Wound healing CRGDK peptide has also been found to promote wound healing by stimulating angiogenesis and collagen synthesis.
Bone regeneration CRGDK peptide has been shown to promote bone regeneration, making it a potential treatment option for conditions such as osteoporosis and bone fractures.
Neuroprotection CRGDK peptide has been found to have neuroprotective properties, which can be beneficial in the treatment of neurological disorders such as Alzheimer's disease and Parkinson's disease.
Anti-cancer effects CRGDK peptide has been shown to have anti-cancer effects by inducing apoptosis (cell death) in cancer cells.
Cardiovascular health CRGDK peptide has also been found to have cardio-protective properties, which can be beneficial in the treatment of cardiovascular diseases such as hypertension and heart failure.state.conformational change allows the integrin to bind to other ECM proteins, leading to the formation of focal adhesions and initiation of downstream signaling events.The interaction between the RGD motif and integrin receptors triggers various intracellular signaling pathways.These pathways regulate cell survival, proliferation, migration, and differentiation.One of the wellstudied signaling pathways is the focal adhesion kinase (FAK) pathway, which activates downstream signaling molecules, including mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K).These signaling events ultimately regulate cellular processes such as cytoskeletal rearrangement, gene expression, and cell cycle progression.The RGD motif-integrin interaction is essential for numerous physiological processes, including embryonic development, tissue homeostasis, and immune response.It is involved in cell adhesion and migration during wound healing, angiogenesis, and tissue regeneration.Dysregulation of the RGD motif-integrin interaction has been implicated in various pathological conditions, including cancer metastasis, fibrosis, and autoimmune diseases.][186][187][188] The interaction between the RGD motif and integrin receptors is a complex and highly regulated process that plays a crucial role in cell adhesion, migration, and signaling.Understanding the detailed information about this interaction provides insights into the mechanisms underlying physiological and pathological processes.Further research in this field may lead to the development of novel therapeutic approaches targeting the RGD motif-integrin interaction for the treatment of various diseases.

| Breast cancer
Breast cancer is a complex illness with several subtypes that have diverse genomic profiles, clinical characteristics, and therapy responses. 189Integrins, a kind of cell surface receptor, are important in cell adhesion, migration, and signaling and are frequently dysregulated in breast cancer.1][192] Understanding the particular integrin expression patterns in various breast cancer subtypes can aid in the development of RGD peptide-based techniques for more effective and tailored breast cancer therapy. 10,73,193 14.24 It is a dangerous subtype with few therapeutic choices and a dismal prognosis.Integrins αvβ3, αvβ5, and α5β1 are widely overexpressed in TNBC, 195,196 and their interaction with RGD peptides has been studied for targeted drug delivery, imaging, and treatment.[197][198][199][200] MDA-MB-231 is a breast cancer cell line generated from a patient with triplenegative/basal-like breast cancer, which is distinguished by the lack of ER, PR, and HER2 expression and has a poor prognosis.Another breast cancer cell line produced by a patient with triple-negative/basal-like breast cancer is MDA-MB-468.It has been found that MDA-MB-231 and MDA-MB-468 cells have integrins αvβ3, αvβ5, and α5β1, which can bind with RGD peptides (Table 6).201-205

| Luminal breast cancer
Luminal breast cancer is distinguished by the presence of hormone receptors (ER and/or PR) and has a better prognosis than TNBC and HER2-positive breast cancer.7][208][209] MCF-7 is a frequently used breast cancer cell line obtained from a patient with luminal A breast cancer, which is distinguished by the presence of estrogen receptor (ER) and/or progesterone receptor (PR) expression and low levels of human epidermal growth factor receptor 2 (HER2).T47D is another breast cancer cell line generated from a luminal A breast cancer patient.MCF-7 and T47D cells have been shown to express integrins αvβ5, and α5β1, which can bind RGD peptides. 151,210,211MCF-7 cells are typically employed as a model for low integrin αvβ3 expression, and similarly, T47D cells exhibit a low level of integrin expression. 52,62,212,213

| Lung cancer
Lung cancer is a diverse collection of cancers that may be divided into two types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).NSCLC is further classified into three major subtypes: adenocarcinoma, squamous cell carcinoma, and giant cell carcinoma.SCLC is distinguished by its fast development and early metastasis. 214,2157][218] These interactions could be used in targeted drug delivery and imaging applications, highlighting the promise of RGD peptides for lung cancer targeted treatment.0][221] These cells have been shown to express integrins αvβ3 and αvβ5, which can bind to RGD peptides.

| Cervical cancer
Cervical cancer is the fourth most frequent cancer in women globally, with HPV infection being the leading risk factor.Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the two primary histological subtypes of cervical cancer. 222,223Several integrins have been shown to interact with RGD peptides, adding to the complexity and heterogeneity of cervical cancer.26]228 Due to its different binding specificity from the other mentioned integrins, Integrin α2β1 does not directly interact with classical linear/cyclic-RGD peptides, but studies suggest that it may be involved indirectly through crosstalk/signaling pathways related to cervical cancer progression mediated by other RGD-binding integrins such as α5β1.0][231] The use of RGD-based inhibitors to target these integrins provides a promising treatment option for cervical cancer, with the potential to enhance patient outcomes and lessen the burden of this deadly illness.RGD peptides, on the other hand, have been demonstrated to interact with integrins αvβ3 and αvβ5, particularly binding to fibronectin in cervical cancer cell lines such as HeLa (SCC) and SiHa (SCC). 217,232

| Colorectal cancer
Colorectal cancer (CRC) is a complex disease with several molecular subgroups that can interact with RGD peptides. 10,233,234The interaction of integrins with RGD peptides is important in the development, metastasis, and angiogenesis of colorectal cancer and colon cancer.][236][237] Accordingly, targeting these integrins and their interactions with RGD peptides may constitute a viable therapeutic method for the treatment of CRC.Integrin αvβ3 is significantly expressed in CRC and has been linked to tumor growth, angiogenesis, and metastasis.The interaction between and RGD peptides increases cell adhesion, migration, and invasion, which contributes to CRC cell aggression.Inhibiting the αvβ3-RGD connection has been demonstrated in preclinical models to inhibit tumor development and angiogenesis, indicating that targeting this integrin may be a potential treatment approach for CRC.Another RGD-binding integrin that is increased in CRC is integrin αvβ5.It has been associated with cell adhesion, migration, and invasion regulation, and with the activation of growth factor signaling pathways such as the VEGF pathway.Targeting the αvβ5-RGD connection might aid in the inhibition of tumor development and angiogenesis in CRC.Integrin expression and interactions with RGD peptides may change between cell lines and subtypes.HCT116, HT-29, SW620, Caco-2, LoVo, LS174T, DLD-1, SW480, and Colo205 colorectal cancer cell lines contain integrin αvβ3, which can interact with RGD peptides. 234,238The RKO cell line has been demonstrated to interact with RGD peptides, which can attach to integrin αvβ5. 239,240

| Liver cancer
Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combination hepatocellularcholangiocarcinoma (cHCC-CC) are all subtypes of liver cancer.The interaction between integrins and RGD peptides is critical in the development, metastasis, and angiogenesis of liver cancer.][243][244] These integrins have been shown to interact with RGD peptides in several liver cancer cell lines.These interactions contribute to tumor growth, metastasis, angiogenesis, and therapy resistance, making them attractive therapeutic targets for the treatment of liver cancer.Integrins αvβ3, αvβ5, and α5β1 are expressed by HepG2, and Huh7 (well-established HCC cell lines). 245-247

| Pancreatic cancer
Pancreatic cancer is a formidable adversary in the world of oncology, characterized by its aggressive nature, limited treatment options, and poor prognosis.Pancreatic cancer is a very aggressive and diverse disease, with pancreatic ductal adenocarcinoma (PDAC) being the most frequent subtype.The search for innovative approaches to combat this deadly disease has led researchers to explore the application of RGD peptides, which have shown promise in targeting integrins-a group of cell surface receptors that play pivotal roles in tumor growth, invasion, angiogenesis, metastasis, and therapy resistance. 248In pancreatic cancer, the dysregulation of integrin expression on cancer cells has been extensively studied.Specifically, integrins αvβ3, αvβ5, and αvβ6 have been implicated in pancreatic cancer progression, making them attractive therapeutic targets. 13][255][256][257][258] One promising approach involves utilizing RGD peptides with high binding affinity for integrins, particularly αvβ3, to enhance drug delivery specificity.RGD peptides have been incorporated into liposomal drug carriers, allowing the targeted delivery of anticancer therapeutics directly to pancreatic cancer cells.This modification enhances the tumor specificity of vesicles, increasing the precision of treatment. 13RGD-conjugated albumin nanoparticles have shown promise as delivery vehicles for therapeutic agents in pancreatic cancer.These nanoparticles, by targeting integrin avβ3 receptors on pancreatic cancer cells, enhance drug penetration, improve antitumor efficacy, and inhibit tumor growth and metastasis. 259RGD peptides have also been employed in conjunction with gemcitabine, a standard drug for pancreatic cancer treatment, to enhance drug penetration into tumors.The coadministration of GEM and RGD peptides has demonstrated effectiveness in reducing tumor size, particularly in cell line-based xenografts, emphasizing the potential clinical utility of this approach 260 In the realm of diagnostic imaging, RGD peptides have been utilized to improve the labeling and uptake of superparamagnetic iron oxide (SPIO) nanoparticles in pancreatic cancer cells.This approach enhances the sensitivity of pancreatic cancer imaging, aiding in early detection and precise evaluation. 261Another innovative application of RGD in pancreatic cancer involves using a quantum dots-RGD probe as a photosensitizer in photodynamic therapy (PDT).This approach inhibits cell proliferation and induces apoptosis in pancreatic carcinoma cells, offering a promising avenue for clinical treatment. 262he application of RGD peptide in pancreatic cancer has emerged as a multifaceted approach encompassing targeted drug delivery, tumor-selective immunotherapies, photodynamic therapy, diagnostic imaging, and more.By targeting integrins, RGD peptides offer a promising avenue to enhance the specificity and efficacy of pancreatic cancer diagnosis and therapy.However, continued research is imperative to fully realize the potential of RGD-based approaches in combating this challenging disease.

| Kidney cancer
Kidney cancer, commonly known as cell carcinoma (RCC), is a diverse group of malignancies that develop from renal tubular epithelial cells.RCC is classified into four subtypes: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), and collecting duct carcinoma (CDC).Each subtype has different histological characteristics, molecular changes, and clinical consequences. 263,264he most prevalent subtype of RCC is ccRCC.It is distinguished by transparent cytoplasm and a well-defined cell membrane.The deletion of the von Hippel-Lindau (VHL) tumor suppressor gene, which leads to the stability of hypoxia-inducible factors (HIFs) and the stimulation of angiogenesis, is the most prevalent genetic change in ccRCC.6][267] RGD peptides may reduce cell adhesion, migration, and invasion in ccRCC cell lines such as 786-O and A498, by targeting these integrins.The second most prevalent kind of RCC is pRCC.The presence of papillary structures bordered by cuboidal or columnar cells marks it.pRCC is classified into two subtypes: Type 1, which has a better prognosis, and Type 2, which is more aggressive and has a worse prognosis. 263,264he prognosis for CDC is poor, with a high prevalence of metastasis and resistance to traditional therapy. 263,264here is little known about the roles of integrins and RGD peptides in chRCC, and CDC.Integrins such as αvβ3 and αvβ5 may, however, have a role in both pRCC, chRCC and CDC, as they are implicated in cell adhesion, migration, and invasion in other RCC subtypes. 9,26815 | CONCLUSION Integrins are a kind of cell adhesion molecule that is required for the growth and spread of cancer.By targeting these molecules with RGD peptides, researchers were able to selectively deliver drugs to cancer cells and the tumor vasculature while preventing injury to healthy organs.This technique has recently shown a lot of promise, with RGD-functionalized drug carriers demonstrating increased efficacy and lower toxicity when compared to traditional chemotherapy.RGD-functionalized drug carriers have also been shown to improve therapeutic efficacy by increasing medicine absorption and retention inside the tumor microenvironment.Because different cancer types may require different treatments or dosages, the precision of this method allows for the development of individualized treatment strategies.RGD peptides and their conjugates can help detect and track the progression of cancer by serving as imaging agents and improving therapy administration.RGD-conjugates are expected to become a more important weapon in the fight against cancer as research in this field advances.

F I G U R E 1
Examples of RGD analouges.

F I G U R E 3
Possible benefits and challenges of RGD peptides.

F I G U R E 4 | 11 of 44 T A B L E 2
Stucture of some RGD-peptides.Cilengitide in preclinical studies.the study's safety run-in:-To determine the maximum tolerated dose (MTD) of cilengitide in combination with cetuximab, and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine).Primary objective of the study's randomization part:-To assess the efficacy of cilengitide in combination with cetuximab and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine) compared to cetuximab and platinum-based chemotherapy alone in terms of progression-free survival (PFS) time.Study design and plan:This is a multicenter, open-label, randomized, and controlled phase II study with a safety run-in part in subjects with advanced non-small cell lung cancer (NSCLC).During the safety run-in, the regimen was intensified stepwise by cohort (cilengitide intravenous \[iv\] 1000 milligram \[mg\] to 2000 mg twice a week) in a classical 3 + 3 subjects (for each platinumbased chemotherapy regimens separately) approach with predefined dose-and schedule reduction rules.

4 (
dated 20 December 2010): â€¢ Group A: Cilengitide 2000 mg once weekly (Days 1, 8, and 15 of every 3-week chemotherapy cycle) in combination with cetuximab and platinum-based chemotherapy that will consist of the following: * Cetuximab once weekly (Days 1, 8, and 15), plus cisplatin on Day 1 and vinorelbine on Days 1 and 8 of every 3-week chemotherapy cycle, or * Cetuximab once weekly (Days 1, 8, and 15), plus cisplatin on Day 1 and gemcitabine on Days 1 and 8 of every 3-week chemotherapy cycle.
this clinical research study is to find the highest tolerable dose of DNX-2401 that can be injected directly into brain tumors and into the surrounding brain tissue where tumor cells can multiply.A second goal is to study how the new drug DNX-2401 affects brain tumor cells and the body in general.this research study is to get information from volunteers without cancer and patients with cancer who have received a new investigational study agent called, "\ [F-18\] RGDK5," to evaluate biodistribution and dosimetry for the study agent and determine F-18 RGD-K5 uptake in angiogenic tumor.the system.two-staged clinical trial to investigate the feasibility of intraoperative fluorescence imaging (FLI) to adequately assess tumor margins in patients with oral cancer using cRGD-, unicentric, uncontrolled.Intratumoral injection or intramural (into the resected tumor cavity) of DNX2401

2 .
Secondary endpoint(s): To expand the safety database of \ [F-18\]RGD-K5 and to correlate the parameters from the image study to clinical treatment response and prognosis.II study The primary objective for this study is * To explore the usefulness of \[F-18\]RGD-K5 PET/CT to predict efficacy or early response to AvastinÂ® (the antiangiogenesis drug) plus chemotherapy treatment before the full course of treatment is completed The secondary objectives for this study are: * To continue safety evaluation by collection of safety data from all patients * To gain experience with \[F-18\]RGD-K5 PET/CT in order to improve the study design and conduct of future studies Design: An open label, non-randomized, uncontrolled, single group assignment, pilot efficacy study Duration: Screening visit (3-4 h), pre-treatment imaging visit of \[F-18\]RGD-K5 PET/CT (\ ~ 3-4 h) and the standard \ [F-18\]FDG PET/CT (\ ~ 3-4 h) or diagnostic CT, followed by two \[F-18\]RGD-K5 PET/CT scans, one after the second but before the third AvastinÂ® treatment, and one after the fourth but before the fifth AvastinÂ® treatment, and a follow-up standard \[F-18\]FDG PET (\ ~ 3-4 h or diagnostic CT.Procedures: Informed consent, collection of demographic information, medical history, blood labs, physical examination, vital signs, ECGs, three sets of \[F-18\] RGD-K5 dosing and imaging scans including pretreatment, early mid-treatment, and later mid-treatment, concomitant medication collection, adverse event monitoring, and assessment of tumor response to treatment Patients: Approximately forty 38patients with nonsquamous non-small cell lung cancer, metastatic breast cancer, metastatic colon or rectum cancer who will receive chemotherapy plus AvastinÂ®.This allows for approximately 30 evaluable patients to complete this study at approximately four to eight sites internationally

T A B L E 6
The probable integrins in different cancers which could interact with RGD peptide.breast cancer (TNBC) MDA-MB-231 and MDA-MB-468 αvβ3, αvβ5, and α5β1 Luminal breast cancer MCF-7, and T47D αvβ3, αvβ5, and α5β1 Lung cancer Non-small cell lung cancer (NSCLC) A549, H1299, H460, HCC827, PC-9 and H1975 αvβ3 and αvβ5 Small cell lung cancer (αvβ3, αvβ5, and α5β1 Pancreatic cancer Pancreatic ductal adenocarcinoma (PDAC) PANC-1, MIA PaCa-2, BxPC-3 and AsPC-1 αvβ3, αvβ5, and α5β1 Renal cell carcinoma (RCC) Clear cell RCC (ccRCC) 786-O and A498 αvβ3, αvβ5, and α5β1 | 35 of 44 trial is studying the side effects and best dose of cediranib maleate when given together with cilengitide in treating patients with progressive or recurrent glioblastoma.Cediranib maleate and cilengitide may stop the growth of tumor cells by blocking blood flow to the tumor.Giving cediranib maleate together with cilengitide may kill more tumor cells.trial studies how well cilengitide works in treating younger patients with recurrent or progressive high-grade glioma that has not responded to standard therapy.Cilengitide may stop the growth of tumor cells by blocking blood flow to the tumor.trial is studying the side effects and best dose of cilengitide in treating children with recurrent, progressive, or refractory primary CNS tumors.Cilengitide may slow the growth of brain cancer cells by stopping blood flow to the tumor.trial studies the side effects and the best dose of cilengitide when given together with paclitaxel weekly in treating patients with solid tumors that have spread nearby or to other areas of the body and cannot be removed by surgery.Cilengitide may stop the growth of tumor cells by blocking blood flow to the tumor.Drugs used in chemotherapy, such as paclitaxel, work in different ways to the stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.Giving cilengitide together with paclitaxel may kill more tumor cells.
TerminatedThe investigators propose to conduct a multicenter, open-label, randomized, phase II study in patients with newly diagnosed glioblastoma (CeCil).Patients should meet all eligibility criteria for the CENTRIC phase III trial at the exception that no MGMT-promoter methylation could be demonstrated.The treatment backbone in both study arms will consist of postoperative radiation therapy with concomitant daily temozolomide, followed by 6 cycles of temozolomide according to a 21 out of 28 days regimen (as in the experimental arm of the RTOG 0525/EORTC 26052-22,053 phase III study).In study arm (A) cilengitide (at a dose of 2000 mg by iv administration, 2x/week) will be added to this backbone while in the second study arm (B), cetuximab will be added (at an initial dose of 400 mg/mÂ 2 administered by intravenous infusion over 2 hours and followed by a weekly dose of 250 mg/mÂ 2 iv over 1 h).In both study arms, treatment will be administered for 52 consecutive treatment weeks.The 1 year overall survival (1y-OS) following randomization will serve as the primary endpoint in both study arms.The MGMT gene promoter is a section of deoxyribonucleic acid (DNA) that acts as a controlling element in the expression of MGMT.Methylation of the MGMT gene promoter has been found to be a predictive marker for benefit from temozolomide (TMZ) treatment.
Cilengitide may stop the growth of brain metastases by blocking blood flow to the tumor.Radiation therapy uses high energy x-rays to kill tumor cells.Giving cilengitide together with radiation therapy may kill more tumor cells.PURPOSE: This Phase I trial is studying the side effects and best dose of cilengitide when given together with whole-brain radiation therapy in treating patients with brain metastases from lung cancer.WithdrawnThe goal of this clinical research study is to learn if cilengitide given in combination with bevacizumab can help to control glioblastoma.The safety of this drug combination will also be studied.Cilengitide is designed to block the flow of blood to cancer cells, which may help to slow or block the growth of cancer.Bevacizumab is designed to block the growth of new blood vessels, which may help to slow or block the growth of cancer. of this study is to evaluate the efficacy of a combined treatment with cilengitide and metronomic oral temozolomide as measured by 6 months overall survival (OS) after diagnosis of relapse or tumor progression in children and adolescents with relapsed or refractory high-grade malignant glioma and diffuse intrinsic pontine glioma.To assess the pharmacokinetics of cilengitide administered as part of the study treatment.Indication and study population for this trial: Treatment of relapsed or refractory high grade gliomas and diffuse intrinsic pontine gliomas in pediatric patients 3 years and\<18 years of age.
Starting one week after the initiation of Cilengitide, RTX(60 Gy, 2 Gy per fraction) with concurrent daily temozolomide (60 mg/m2 p.o.) and daily procarbazine (PCB, 50 mg p.o. if BSA\ < 1.7; 100 mg p.o. if BSA 1.7) is given over a period of 6 weeks (RTX Monday to Friday, both TMZ and PCB 7 days a week).After a break of 4 weeks, adjuvant TMZ (50 mg/m2 p.o in first cycle, 60 mg/m2 p.o. in subsequent cycles) and PCB (50 mg p.o. if BSA \ < 1.7; 100 mg p.o. if BSA 1.7) are then given daily D1 to 20.This TMZ/ PCB cycle is repeated every 28 days over a total period of 6 cycles.T A B L E 3 (Continued)T A B L E 4 RGD peptides in clinical trials.